The broad, long-term objectives of the proposed research are to characterize the function of DNA polymerase beta in mammalian cells and intact animals and to determine if alterations of DNA polymerase beta activity contribute to carcinogenesis. The specific aims of this proposal are threefold: (1) to test the hypothesis that DNA polymerase beta functions in DNA repair, (2) to determine whether the DNA polymerase beta gene is essential to mouse development, and (3) to determine if loss of function of DNA polymerase beta promotes tumorigenesis. Much indirect evidence indicates that DNA polymerase beta functions in DNA repair in mammalian cells. In addition, loss of heterozygosity in the vicinity of the DNA polymerase beta locus is found in many types of human cancers. However, existing evidence does not provide a clear understanding of how aberrant DNA repair contributes to the development of neoplasia. The approach of the proposed project is to use a consistent genetic background to test the precise role of Pol beta in DNA repair and to determine if a Pol beta deficiency results in tumor formation. Cell lines containing targeted disruptions of the Pol beta gene will be engineered and analyzed for their ability to repair damaged DNA. These cell lines will then be used to construct mice containing exactly the same targeted disruption of the Pol gene. We will determine if these mice develop neoplasms at a rate greater than wild type mice. Our strategy has the potential to more clearly define the contribution of aberrant DNA repair to the development of cancer.